CN106573059A

CN106573059A - Method for treating psoriasis patient which received anti-TNF-alpha antibody therapy

Info

Publication number: CN106573059A
Application number: CN201580045672.7A
Authority: CN
Inventors: 中川秀己; 松户泰树
Original assignee: Kirin Amgen Inc
Current assignee: Amgen K A Inc
Priority date: 2014-08-26
Filing date: 2015-08-26
Publication date: 2017-04-19
Also published as: JP6663910B2; CA2962910A1; JP2017527546A; WO2016031250A1; EP3185902A1; AU2015307868B2; KR102427097B1; SG11201701276SA; KR20170045222A; US20170298136A1; MY186840A; EP3185902B1; CA2962910C; AU2015307868A1; EP3185902A4

Abstract

The present invention relates to a therapeutic agent for pustular psoriasis or psoriatic erythroderma that is administered to a psoriasis patient that has been administered with an anti-TNF-alpha antibody. The therapeutic agent comprises an IL-17RA antagonist as an active ingredient. The invention also relates to a therapeutic agent for psoriasis that is administered to a psoriasis patient that cannot be treated with an anti-TNF-alpha antibody, with the therapeutic agent comprising an IL-17RA antagonist as an active ingredient. In addition, the present invention also relates to a method for the treatment of pustular psoriasis or psoriatic erythroderma, comprising administering the IL-17RA antagonist to a psoriasis patient that has been administered with the anti-TNF-alpha antibody; and to a method for the treatment of psoriasis, comprising administering the IL-17RA antagonist to a psoriasis patient that cannot be treated with the anti-TNF-alpha antibody.

Description

Received the Therapeutic Method of the psoriatic of anti-TNF-α antibody therapy

Technical field

The present invention relates to the therapeutic agent of pustular psoriasiss or erythroderma psoriaticum, it is applied to apply and resists The psoriatic of TNF-α antibody, the therapeutic agent is comprising IL-17RA antagonisies as active component；And be related to be applied to not Can with anti-TNF-α antibody treat psoriatic curing psoriasis agent, its include IL-17RA antagonisies as activity into Point.The invention further relates to the Therapeutic Method of pustular psoriasiss or erythroderma psoriaticum, it includes and resist to having applied The psoriatic of TNF-α antibody applies IL-17RA antagonisies；With curing psoriasis method, it is included to can not use anti-tnf-alpha The psoriatic of Antybody therapy applies IL-17RA antagonisies.

Background technology

The excessive generation of cytokine causes numerous inflammatory autoimmune disease to include psoriasises, psoriatic arthritis and asthma Development.The family of interleukin (IL) -17 of cytokine includes 6 family members of following title：IL-17A, IL-17B, IL- 17C, IL-17D, IL-25 (also referred to as IL-17E), and IL-17F.Interleukin-17 A, IL-17F and IL-17A/F are by producing The t helper cell (Th17) of IL-17 cells and show in autoimmune disease model and facilitate the natural of inflammatory response to exempt from The significant proinflammatory cytokine (NPL 1-6) that epidemic disease cell is produced.

Interleukin-17 A, IL-17F and IL-17A/F have multi-effective active, including from epithelial cell, endotheliocyte and into fibre Dimension cell induction pro-inflammatory mediator promotion organization inflammation and destruction；The propagation of neutrophil cell, ripe and chemotaxiss；With it is tree-shaped Cell maturation (NPL 7,8).

Interleukin-2 5 aids in 2 (Th2) cells, eosinophilic granulocyte and basophil to produce by epithelial cell, T-, and More Jing is often related (NPL 9-11) to Th2- type inflammatory pathology such as asthma.Interleukin-17 C is also produced by epithelial cell and should The biological activity of cytokine is studied, but is seemed active similar (NPL 12) to IL-17A and IL-17F.

Interleukin-17 RA is in diversified cell type, including but not limited to fibroblast, epithelial cell and list I types transmembrane receptor (NPL 13) present on nucleuss.Interleukin-17 A, IL-17F, IL-17A/F, IL-17C and IL-25 lead to Cross and stimulation cell effect is combined with IL-17RA.Interleukin-17 A, IL-17F and IL-17A/F are via different poly- IL-17RA/IL- 17RC complexs signal, and IL-17C signals via different poly- IL 17RA/IL-17RE complexs, and IL-25 is via different poly- IL- 17RA/IL-17RB complexs signal (NPL 12,14-17).Interleukin-17 RA blocking represent suppression with autoimmune and Inflammatory diseasess include but is not limited to the new mechanism of psoriasises, the psoriatic arthritis inflammation related to asthma and clinical symptoms.

AM-14 is the IgG2 monoclonal antibodies of people's Chinese hamster ovary celI source property, its combined with human il-17 RA and blocked IL-17A, The biological activity of IL-17F, IL-17A/F heterodimer, and IL-25 participates in various autoimmune diseases and inflammatory disease (NPL 18- 20)。

Quote catalogue

Non-patent literature

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NPL 7：Immunity.2004；21：467-476

NPL 8：J Immunol.1999；162(1)：577-584

NPL 9：Immunological Rev.2008；226：172-190

NPL 10：J Exp Med.2007；204(8)：1837-1847

NPL 11：Immunity.2001；15：985-995

NPL 12：Nat Immunol.2011；12(12)：1159-1166

NPL 13：Cytokine.1997；9(11)：794-800

NPL 14：Nat Immunol.2011；12(12)：1151-1158

NPL 15：J Immunol.2008；181(6)：4299-4310

NPL 16：J Immunol.2008；181(4)：2799-2805

NPL 17：J Immunol.2006；177(1)：36-39

NPL 18：Immunity.2008；28(4)：454-67

NPL 19：J.Allergy.Clin.Immunol.2007；120(6)：1324-31

NPL 20：J Immunol.2005；175(1)：404-12

The content of the invention

Technical problem

It is an object of the invention to provide the therapeutic agent of pustular psoriasiss or erythroderma psoriaticum, it is applied to The psoriatic for applying anti-TNF-α antibody, the therapeutic agent is comprising IL-17RA antagonisies as active component；And administration In the curing psoriasis agent of the psoriatic that can not be treated with anti-TNF-α antibody, it includes IL-17RA antagonisies as activity Composition.The present invention is also intended to provide the Therapeutic Method of pustular psoriasiss or erythroderma psoriaticum, and it is included to having applied The psoriatic for crossing anti-TNF-α antibody applies IL-17RA antagonisies；With curing psoriasis method, it includes anti-to using The psoriatic of TNF-α Antybody therapy applies IL-17RA antagonisies.

Way to solve the problem

The present invention relates to following (1) to (34).

(1) therapeutic agent of pustular psoriasiss or erythroderma psoriaticum, it is applied to have applied anti-tnf-alpha and resists The psoriatic of body, it includes IL-17RA antagonisies as active component.

(2) therapeutic agent described in (1), wherein the anti-TNF-α antibody is at least one is selected from adalimumab, Ying Fu Sharp former times monoclonal antibody, Polyethylene Glycol combine the antibody of match trastuzumab, match trastuzumab and goli mumab.

(3) therapeutic agent described in (1) or (2), wherein the IL-17RA antagonisies be anti-IL-17RA antibody or its Antibody fragment.

(4) therapeutic agent described in (3), wherein the anti-IL-17RA antibody selected from it is following a) and b)：

A) monoclonal antibody, wherein the complementary determining region of the weight chain variable district (hereinafter referred to as VH) of the antibody is (hereinafter referred to as For CDR) 1, CDR2 and CDR3 respectively include SEQ ID NO：1st, the aminoacid sequence shown in 2 and 3, and the antibody is light CDR1, CDR2 and CDR3 of chain variable region (hereinafter referred to as VL) includes respectively SEQ ID NO：4th, the aminoacid sequence shown in 5 and 6 Row；With

B) monoclonal antibody, wherein the VH of the antibody includes SEQ ID NO：The aminoacid sequence shown in 7, and institute The VL for stating antibody includes SEQ ID NO：The aminoacid sequence shown in 8.

(5) clinic of the therapeutic agent described in any one of (1) to (4), wherein patient after the therapeutic agent is applied is total Body impression (hereinafter also referred to CGI) becomes 2 or 1.

(6) the silver bits of the therapeutic agent described in any one in (1) to (5), wherein patient after the therapeutic agent is applied Sick area and Severity Index (hereinafter referred to as PASI) scoring are less than the PASI scorings applied before the therapeutic agent.

(7) curing psoriasis agent, it is applied to the psoriatic that can not be treated with anti-TNF-α antibody, the treatment Agent is comprising IL-17RA antagonisies as active component.

(8) therapeutic agent described in (7), wherein the patient that can not be treated with anti-TNF-α antibody is to described anti- TNF-α antibody is not responding to or the patient inadequate to the anti-TNF-α antibody toleration.

(9) therapeutic agent described in (7) or (8), wherein the anti-TNF-α antibody is selected from adalimumab, Ying Fu Sharp former times monoclonal antibody, Polyethylene Glycol combine at least one of match trastuzumab, match trastuzumab and goli mumab.

(10) therapeutic agent described in any one of (7) to (9), wherein the IL-17RA antagonisies are anti-IL-17RA resisting Body or its antibody fragment.

(11) therapeutic agent described in (10), wherein the anti-IL-17RA antibody selected from it is following a) and b)：

A) monoclonal antibody, wherein CDR1, CDR2 and CDR3 of the VH of the antibody include respectively SEQ ID NO：1st, 2 and The aminoacid sequence shown in 3, and CDR1, CDR2 and CDR3 of the VL of the antibody includes respectively SEQ ID NO：4th, 5 and 6 The aminoacid sequence of middle display；With

(12) therapeutic agent described in any one of (7) to (11), wherein the psoriasises are at least one selected from ordinary The psoriasises of property psoriasises, psoriatic arthritis, pustular psoriasiss, erythroderma psoriaticum and psoriasis punctata.

(13) CGI of the therapeutic agent described in any one of (7) to (12), wherein patient after the therapeutic agent is applied becomes Into 2 or 1.

(14) PASI of the therapeutic agent described in any one of (7) to (13), wherein patient after the therapeutic agent is applied Scoring is less than the PASI scorings applied before the therapeutic agent.

(15) Therapeutic Method of pustular psoriasiss or erythroderma psoriaticum, it is included to having applied anti-tnf-alpha The psoriatic of antibody applies IL-17RA antagonisies.

(16) method described in (15), wherein the anti-TNF-α antibody is selected from adalimumab, Infliximab list Anti-, Polyethylene Glycol combines at least one of match trastuzumab, match trastuzumab and goli mumab.

(17) method described in (15) or (16), wherein the IL-17RA antagonisies be anti-IL-17RA antibody or its Antibody fragment.

(18) method described in (17), wherein the anti-IL-17RA antibody selected from it is following a) and b)：

(19) method described in any one of (15) to (18), wherein the patient is applying the IL-17RA antagonisms CGI after agent becomes 2 or 1.

(20) method described in any one of (15) to (19), wherein patient are after the IL-17RA antagonisies are applied PASI scorings less than the PASI scorings applied before the antagonist.

(21) method described in any one of (15) to (20), wherein applying the IL- with the dosage of 140mg or bigger 17RA antagonisies.

(22) method described in any one of (15) to (21), wherein applying described with the dosage of 140mg or 210mg IL-17RA antagonisies.

(23) method described in any one of (15) to (22), wherein in first day, first week and second week, and its Afterwards once every two weeks, the IL-17RA antagonisies are applied with the dosage of 140mg or 210mg.

(24) curing psoriasis method, it includes to the psoriatic that can not be treated with anti-TNF-α antibody and applies IL- 17RA antagonisies.

(25) method described in (24), wherein the patient that can not be treated with anti-TNF-α antibody is to described anti- Invalid or inadequate to the anti-TNF-α antibody toleration patient of TNF-α antibody.

(26) method described in (24) or (25), wherein the anti-TNF-α antibody is selected from adalimumab, Ying Fu Sharp former times monoclonal antibody, Polyethylene Glycol combine at least one of match trastuzumab, match trastuzumab and goli mumab.

(27) method described in any one of (24) to (26), wherein the IL-17RA antagonisies are anti-IL-17RA resisting Body or its antibody fragment.

(28) method described in (27), wherein the anti-IL-17RA antibody selected from it is following a) and b)：

(29) method described in any one of (24) to (28), wherein the psoriasises be selected from psoriasis vulgarises, At least one of psoriatic arthritis, pustular psoriasiss, erythroderma psoriaticum and psoriasis punctata.

(30) method described in any one of (24) to (29), wherein the patient is applying the IL-17RA antagonisms CGI after agent becomes 2 or 1.

(31) method described in any one of (24) to (30), wherein patient are after the IL-17RA antagonisies are applied PASI scorings less than the PASI scorings applied before the antagonist.

(32) method described in any one of (24) to (31), wherein applying the IL- with the dosage of 140mg or bigger 17RA antagonisies.

(33) method described in any one of (24) to (32), wherein applying described with the dosage of 140mg or 210mg IL-17RA antagonisies.

(34) method described in any one of (24) to (33), wherein in first day, first week and second week, and its Afterwards once every two weeks, the IL-17RA antagonisies are applied with the dosage of 140mg or 210mg.

The advantageous effects of invention

The present invention can provide the therapeutic agent of pustular psoriasiss or erythroderma psoriaticum, and it is applied to apply The psoriatic of anti-TNF-α antibody is crossed, the therapeutic agent is comprising IL-17RA antagonisies as active component；Be applied to not Can with anti-TNF-α antibody treat psoriatic curing psoriasis agent, its include IL-17RA antagonisies as activity into Point.The present invention can also provide the Therapeutic Method of pustular psoriasiss or erythroderma psoriaticum, and it is included to having applied The psoriatic of anti-TNF-α antibody applies IL-17RA antagonisies；With curing psoriasis method, it includes anti-to using The psoriatic of TNF-α Antybody therapy applies IL-17RA antagonisies.

Description of the drawings

[Fig. 1] Fig. 1 (A) to 1 (C) shows AM-14 to having applied the pustular psoriasiss patient of anti-TNF-α antibody Response to treatment.The longitudinal axis represents clinical global impression, and transverse axis represents the time (week) after first time AM-14 is applied.(A) to (C) It is respectively the result of experimenter A to C.

[Fig. 2] Fig. 2 (D) and 2 (E) show AM-14 to having applied the pustular psoriasiss patient of anti-TNF-α antibody Response to treatment.The longitudinal axis represents clinical global impression, and transverse axis represents the time (week) after first time AM-14 is applied.And (E) (D) It is respectively the result of experimenter D and E.

[Fig. 3] Fig. 3 shows AM-14 to having applied the treatment of the erythroderma psoriaticum patient of anti-TNF-α antibody Effect.The longitudinal axis represents PASI scorings, and transverse axis represents the time (week) after first time AM-14 is applied.That what is applied also is indicated as applying for 0 week First day.The result of experimenter F, G and H is respectively with the depicted as solid lines with dark circles, plus sige and minus sign symbol.

Specific embodiment

The present invention relates to the therapeutic agent of pustular psoriasiss or erythroderma psoriaticum, it is applied to apply and resists The psoriatic of tumor necrosis factor-alpha (hereinafter referred to as " anti-tnf-alpha ") antibody, the therapeutic agent includes IL-17RA antagonisies As active component；And be related to be applied to the curing psoriasis agent of the psoriatic that can not be treated with anti-TNF-α antibody, its bag Antagonist containing IL-17RA is used as active component (below, the therapeutic agent also will be referred to collectively as " therapeutic agent of the present invention ").

The invention further relates to the Therapeutic Method of pustular psoriasiss or erythroderma psoriaticum, it is included to having applied The psoriatic of anti-TNF-α antibody applies IL-17RA antagonisies；And it is related to curing psoriasis method, it is included to can not use The psoriatic of anti-TNF-α antibody treatment applies IL-17RA antagonisies, and (below, the Therapeutic Method also will be referred to collectively as " this Bright Therapeutic Method ").

The anti-TNF-α antibody has no particular limits in the present invention, as long as it is the antibody to anti-tnf-alpha. The anti-TNF-α antibody preferably resists the antibody of humanTNF-α.The instantiation of the anti-human TNF-α antibody includes Ying Fuli Former times monoclonal antibody, adalimumab, Polyethylene Glycol combine match trastuzumab, match trastuzumab, goli mumab etc..

Psoriasises are chronic dermatosis, and in clinical practice, psoriasises are divided into five types according to symptom and performance position, That is psoriasis vulgarises, psoriatic arthritis, pustular psoriasiss, erythroderma psoriaticum and psoriasis punctata.It is common Psoriasises are characterized with skin erythema with pachyderma, sharpness of border (speckle) and squama.Psoriatic arthritis are except skin There is the disorderly chronic inflammatory disease of joint, stndon sheath, tendon attachment portion and skeleton axilale Deng outside.Pustular psoriasiss are with red The erythra of shaping referred to as pustule is characterized on speckle.Erythroderma psoriaticum is with skin rash and rubescent with diffusivity or squama is Feature.Psoriasis punctata is characterized with the little psoriasis pustulosa rash that there is diameter 1cm on trunk, lower limb and arm.

The psoriatic example relevant with the present invention includes psoriasis vulgarises, psoriatic arthritis (also referred to as psoriasises Property arthrosiss), pustular psoriasiss, erythroderma psoriaticum, psoriasis punctata etc..Preferably psoriasis vulgarises, silver The sick arthritis of bits, pustular psoriasiss and erythroderma psoriaticum.More preferably the psoriasis vulgarises of moderate to severe and Psoriatic arthritis, and pustular psoriasiss and erythroderma psoriaticum.Further preferably pustular psoriasiss and silver Bits characteristic of disease erythroderma.The psoriasises relevant with the present invention include the concurrent psoriasises of various above-mentioned psoriasises types, and also wrap Include nail psoriasis.

The psoriasises can be the form for being related to psoriasis in plaques, and preferably be related to moderate to severe speckle type silver The form of bits disease.The psoriasises can be limitations or can affect whole body.The instantiation of Local Psoriasis includes head Skin psoriasises etc..The psoriasises for being related to plaque psoriasis are primarily referred to as being related to the psoriasis vulgarises of plaque psoriasis, and remove Outside plaque psoriasis, also including the psoriatic arthritis for being related to joint symptoms.

Pustular psoriasiss can the general hair style pustular psoriasiss of pustule extensively occurred or pus occur in a small range The topical type pustular psoriasiss of bleb, and preferably general hair style pustular psoriasiss.The concrete reality of general hair style pustular psoriasiss Example includes acute general hair style pustular psoriasiss, general hair style pustular psoriasiss, ring-type and circular pustular psoriasiss, herpess sample Impetigo, no fever type impetigo herpetiformis, teenager and child's pustular psoriasiss etc..Topical type pustular psoriasiss Instantiation includes palmoplantar pustulosises, acrodermatitis continua, temporary transient limitation impetiginization of psoriasis vulgarises, etc..

The therapeutic agent of the present invention is referred to can reduce pustular silver in the psoriatic for applied anti-TNF-α antibody The medicine of the order of severity of bits disease or erythroderma psoriaticum.The therapeutic agent of the present invention also refers to and can not use anti-TNF-α antibody The therapeutic agent of severity of psoriasis is reduced in the psoriatic for the treatment of.

The Therapeutic Method of the present invention refers to and pustular can be reduced in the psoriatic for applied anti-TNF-α antibody The method of the order of severity of psoriasises or erythroderma psoriaticum.The method of the present invention also refers to can not use anti-TNF-α antibody The Therapeutic Method of severity of psoriasis is reduced in the psoriatic for the treatment of.

In the present invention, for term " having applied anti-TNF-α antibody ", when it is with regard to applying the anti-TNF- Alpha antibodies have no particular limits, as long as it is in the therapeutic agent or subject treatment method that first time applies the present invention to patient IL-17RA antagonisies before be applied to the patient.After applying the anti-TNF-α antibody, can apply in first time Other drugs are applied before the therapeutic agent or the IL-17RA antagonisies of the present invention.

The example of the psoriatic that can not be treated with anti-TNF-α antibody is included when anti-to psoriatic's administration The inadequate patient of (constitutional fails or secondary failure) invalid to the anti-TNF-α antibody during TNF-α antibody or toleration.

When used herein, " constitutional failure " refers to the drug effect applied for the first time not enough, and " secondary failure " is referred to The curative effect of applied medicine weakens during continuous administration.In addition, " toleration is inadequate " refers to that the medicine because being applied occurs The serious side effects of the intolerable degree of patient.

Any improvement of psoriasises symptom can be judged using known method.For example, improving can pass through to apply the present invention's After the IL-17RA antagonisies in the Therapeutic Method of therapeutic agent or the present invention scoring of various indexs relative to reducing before applying, Particular by psoriasises area and Severity Index (hereinafter referred to as " PASI "), nail psoriasis Severity Index (hereinafter referred to as " NAPSI "), psoriasises scalp Severity Index (hereinafter referred to as " PSSI ") or it is static when Physician global assessment (hereinafter referred to as " sPGA ") scoring reduce；Life quality in patients with psoriasis (hereinafter referred to as QOL) improves；Etc. judging.

PASI indicates the order of severity of psoriatic skin symptom, and it can be according to [http：//www.kyowa- Kirin.co.jp/kayumi/kansen/jinjo_08.html] described in method tolerance.NAPSI indicates nail psoriasis The order of severity of symptom, it can according to Rich etc. (J.Am.Acad.Dermatol.vol.49, number 2, p.206-212 (2003)) the method tolerance of description.PSSI indicates the psoriatic order of severity of scalp, and it can be according to Leonardi etc. (J.Engl.J.Med.2012；366：1190-9) the method tolerance of description.SPGA is indicated by the skin symptom of Physician Global Assessment The order of severity, it can according to H.N.Viswanathan etc. (Journal of Dermatological Treatment, 2014 Online release (the doi of on July 31,：10.3109/09546634.2014.943687)) the method tolerance of description.QOL is utilized , used as index, it can be according to (the Journal of Dermatological Treatment such as H.N.Viswanathan for DLQI Posted, the Online release (doi of on July 31st, 2014：10.3109/09546634.2014.943687)) the method degree of description Amount.

The effect of the IL-17RA antagonisies in the therapeutic agent or subject treatment method of the present invention passes through clinical global impression (hereinafter referred to as CGI) is evaluated, and the CGI presses level Four [1：Go down, 2：Improve, 3：It is constant, 4：Increase] one of judge from for the first time The change of the psoriatic skin symptom that the antagonist rises is applied, accordingly it is also possible to become 1 (going down) or 2 (improvement) from CGI The fact confirms effect.

In addition to the method described above, improving for pustular psoriasiss symptom can also be from the therapeutic agent or institute for applying the present invention State the degree scoring after antagonist the fact that reduction etc. to confirm relative to before administration.The degree scoring is by suffering from The skin symptom (erythema, pustule, edema) of person evaluate and to systemic inflammatory inspection finding (fever, numeration of leukocyte, Serum CRP level, and serum albumin level) scoring being scored and obtained, and degree scoring can be based on " pustule Property psoriasises (general hair style) clinical practice guideline 2010：Including with reference to the therapeutic strategy (Clinical including TNF-α inhibitor Practice Guideline 2010for pustular psoriasis(generalized type)：therapeutic Strategy including incorporation of TNF-alpha inhibitor) (Iwatsuki Keiji etc.) " in The standard of the order of severity of the pustular psoriasiss of description and calculate.

Specifically, the example that erythroderma psoriaticum symptom improves includes applying relative after the therapeutic agent or antagonist PASI scorings reduction etc. before administration.More specifically, the improvement of erythroderma psoriaticum symptom refers to the administration treatment After agent PASI scoring relative to before the administration reduce by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, preferably reduce by 100%.

Term is applied and may refer to single administration as used herein or repeatedly apply (hereinafter also referred to " continuously apply With ").Additionally, when the scoring of above-mentioned severity of psoriasis is indicated before and after comparing administration, may compare the scoring applied for the first time Scoring after applying with single or multiple time, or the scoring in comparable continuous administration between suitable two points.

The dosage of the IL-17RA antagonisies in the therapeutic agent and the inventive method of the present invention has no particular limits, and Desirably 70mg or higher, is more desirable to 140mg or higher, highly desirable 210mg or higher.In therapeutic agent described in continuous administration or short of money During anti-agent, the dosage can be suitably increased or decreased.

The dosing interval of the therapeutic agent and antagonist has no particular limits.Specifically, for example, the therapeutic agent and Antagonist can be applied in first day (hereinafter also referred to 0 week), first week and second week, thereafter once every two weeks or every four weeks one It is secondary.Dosing interval can also proper extension, or can shorten.

The administration phase of the therapeutic agent and antagonist has no particular limits.Specifically, for example, the therapeutic agent and short of money Anti-agent can be applied 10,20,30,40 or 50 weeks or be longer than 50 weeks after first time applies, and preferably administration is longer than 50 weeks.It is described Administration phase may include the rest period.

IL-17RA in the present invention is not limited to particular types, and preferably human il-17 RA.The IL-17RA antagonisms of the present invention Agent can be any antagonist, if it suppress IL-17RA and IL-17RA parts (such as IL-17A, IL-17F, IL-17A/F, IL-25 etc.) between interaction.Specifically, for example, the IL-17RA antagonisies can have to suppress IL- The active antagonist of 17RA and the ligand binding, the work with the IL-17RA activation for suppressing to be started by the ligand binding Property antagonist or form the active antagonist of heterodimer with suppressing to be associated between IL-17RA and receptor.

The IL-17RA antagonisies can have any form, including, for example, small molecule, antibody, antibody fragment, antigen knot Close fragment, siRNA, antisense oligomer etc..Preferably, the antagonist is antibody or antibody fragment.

Include anti-IL-17RA antibody, anti-IL-17A antibody, anti-IL- as the instantiation of the antibody of IL-17RA antagonisies 17F antibody, anti-IL-17A/F antibody and anti-IL-17E antibody.It is preferred that anti-IL-17RA antibody.

Antibody used can be any one of monoclonal antibody and polyclonal antibody in the present invention, and preferably with it is single The monoclonal antibody that epi-position is combined.

The antibody can be the monoclonal antibody produced by hybridoma or the heredity weight produced by gene recombination technology Group antibody.The example of the genetically recombinant antibody includes that mouse antibodies, rat Ab, people's chimeric antibody (are hereinafter referred to as fitted together to Antibody), humanized antibody [also referred to as people's complementary determining region (CDR) grafted antibody] and human antibody；And in order to reduce in the mankind In immunogenicity, preferably use chimeric antibody, humanized antibody or human antibody.

Specifically, monoclonal antibody of the invention can be the antibody selected from following (A) to (B)：

(A) monoclonal antibody, wherein CDR1, CDR2 and CDR3 of the weight chain variable district (hereinafter referred to as VH) of the antibody point Bao Han not SEQ ID NO：1st, the aminoacid sequence shown in 2 and 3, and the light chain variable district (hereinafter referred to as VL) of the antibody CDR1, CDR2 and CDR3 respectively include SEQ ID NO：4th, the aminoacid sequence shown in 5 and 6；With

(B) monoclonal antibody, wherein the VH of the antibody includes SEQ ID NO：The aminoacid sequence shown in 7, and The VL of the antibody includes SEQ ID NO：The aminoacid sequence shown in 8.

In the present invention, CDR1, CDR2 and CDR3 of the VH in antibody includes respectively SEQ ID NO：1st, show in 2 and 3 Aminoacid sequence and the antibody VL CDR1, CDR2 and CDR3 respectively include SEQ ID NO：4th, the ammonia shown in 5 and 6 VH in the monoclonal antibody or antibody of base acid sequence includes SEQ ID NO：The aminoacid sequence shown in 7 and the antibody VL includes SEQ ID NO：The monoclonal antibody of the aminoacid sequence shown in 8 includes anti-human IL-17RA human monoclonal antibodies AM_H14/AM_L14 (WO 2008/054603) and anti-human IL-17RA human antibodies AM-14 of genetic recombination (also referred to as brodalumab) Deng.

In the present invention, monoclonal antibody refers to the antibody-producting cell secretion by single clone and only recognizes a table Position (antigenic determinant) and constitute the consistent antibody of aminoacid sequence (primary structure) of the monoclonal antibody.

Epi-position refer to monoclonal antibody recognize with combine single amino acids sequence, be made up of the aminoacid sequence three Dimension structure, combine modification the residue such as aminoacid sequence of sugar chain, glycolipid, saccharose lipid, amino, carboxyl, phosphoric acid, sulphuric acid etc., The three dimensional structure constituted with the aminoacid sequence that residue is modified by the combination.The three dimensional structure is naturally occurring protein Three dimensional structure, it refers to the three dimensional structure being made up of the protein expressed in the cell or on cell membrane.

In the present invention, the antibody molecule is also referred to as immunoglobulin (hereinafter referred to as " Ig ").Human antibodies according to Difference between molecular structure is divided into IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4 and IgM isotype.In amino IgG1, IgG2, IgG3 and IgG4 of acid sequence aspect very high homology relative to each other is also referred to collectively as IgG.

In the present invention, the antibody molecule is by referred to as heavy chain (hereinafter referred to as H chains) and the polypeptide of light chain (hereinafter referred to as L chains) Composition.

Additionally, respectively, H chains are made up of from N- ends VH and H chains constant region (also referred to as CH), and L chains are from N- ends by VL With L chains constant region (also referred to as CL) composition.

Chimeric antibody is referred to and is made up of the VH and VL of the antibody for stemming from non-human animal and the CH and CL of human antibodies Antibody.The animal species in the variable region source have no particular limits, as long as it is to can be used to prepare the animal of hybridoma , such as mice, rat, hamster, rabbit etc..

Humanized antibody is the VH that human antibodies are transplanted to by the CDR of VH and VL by non-human animal's antibody is stemmed from With the antibody (people's CDR grafted antibody) obtained in the appropriate location of VL.

Human antibodies refer to naturally occurring antibody in human body, and also include from human antibodies phage library or produce the mankind The antibody that the transgenic animal of antibody obtain, it is based on advanced skill newest in genetic engineering, cell engineering and development engineering Art and prepare.

In the present invention, the type of the antibody fragment has no particular limits, and the example may include Fab, Fab ', F (ab’)₂, scFv, double antibody, dsFv, the peptide containing CDR etc..

The therapeutic agent of the present invention can be the therapeutic agent for only including the IL-17RA antagonisies as active component, however, Preferably it is provided as generally mixing and by pharmaceutical technology field with one or more pharmacology acceptable carrier The pharmaceutical preparation of any known method manufacture.The instantiation of the pharmaceutical preparation is included comprising 140mg/mL genetic recombination L-Glutamic Acid, the L-PROLINE of 3% (w/v) of anti-human IL-17RA human antibodies AM-14 as active component and with 10mmol/L The pharmaceutical preparation prepared together with the polysorbate20 of 0.010% (w/v) as additive etc..The pharmaceutical preparation is also wrapped The pharmaceutical preparation of pH 4.8 is included, anti-human IL-17RA human antibodies AM-14 of the genetic recombination that it includes 140mg/mL are simultaneously also included The L-Glutamic Acid of 30mmol/L, the L-PROLINE of 2.4% (w/v) and 0.01% (w/v) polysorbate as additive 20.The pharmaceutical preparation can for example by the method manufacture described in WO 2011/088120.

The route of administration of the IL-17RA antagonisies with regard to applying in the therapeutic agent or the inventive method of the present invention, preferably makes The most effective person during the treatment.The instantiation of route of administration is included in oral administration or parenteral such as mouth, air flue, Internal rectum, subcutaneous, intramuscular or intravenous administration, preferably subcutaneously and intravenously, more preferably subcutaneous administration.The reality of form of medication Example includes spray, capsule, tablet, powder agent, granule, syrup, Emulsion, suppository, injection, unguentum, paster agent etc., Injection is preferred.

The therapeutic agent of the present invention or the doser of IL-17RA antagonisies can be suitably selected during treating.Example bag Pre-charge injector and automatic injector are included, however, described device is not limited to the example.

Embodiment 1

III clinical trial phase of recombinant anti human IL-17RA human antibodies AM-14 in Japan

Table 1 provides III phase of recombinant anti human IL-17RA human antibodies AM-14 (hereinafter referred to as " AM-14 ") in Japan The summary of clinical trial (hereinafter also referred to as " clinical trial ").The pustular psoriasiss patient of the condition provided in table 2 is provided Or erythroderma psoriaticum patient is chosen as clinical trial experimenter, and in the safety and treatment of long term administration post-evaluation AM-14 Effect.Each experimenter applied the AM-14 of 140mg at the 1st day, the 1st week and the 2nd week, thereafter once every two weeks until the 50th week.It is right There is no the experimenter of abundant effect when at the 4th week, increasing dosage simultaneously applies every two weeks from the 6th week 210mg's AM-14.The clinical trial upon administration the 52nd week when terminate.

AM-14 has the antibody variable region amino acid sequence described in WO 2008/054603, and using conventional method system For into the recombinant human antibody for being obtained from Chinese hamster ovary celI.

[table 1]

[table 2]

Embodiment 2

Response to treatment of the AM-14 to the pustule patient of administering anti-TNF-Alpha antibodies

Five experimenters for participating in the clinical trial of embodiment 1 had applied the anti-TNF-α antibody.Measure these to receive The clinical global impression (hereinafter referred to as CGI) of examination person, it is demonstrated by from first time applies AM-14 through time course Psoriatic skin symptom changes.The result for obtaining is presented in Fig. 1 (A) to 1 (C), 2 (D) and 2 (E).CGI with 1 to 4 grade display, Represent respectively go down, improve, it is constant and increase, judged by doctor.

As shown in Fig. 1 (A) to 1 (C), 2 (D) and 2 (E), AM-14 can be to having applied the anti-TNF-α antibody Five pustule patients in four apply 50 weeks, and CGI when the 52nd week is less than 2.Prove as described above, AM-14 shows Go out the pustule patient to having applied the anti-TNF-α antibody and there is response to treatment.

Embodiment 3

The response to treatment of pustular psoriasiss patients of the AM-14 to being treated with anti-TNF-α antibody

Table 3 provides the curing psoriasis agent in five experimenters of the examination of embodiment 2 and uses history.Experimenter B in table 3 The curing psoriasis agent is used with shown order with D.Three experimenters A, C and E are using infliximab until facing Before applying AM-14.Infliximab and adalimumab be anti-human TNF-α antibody (infliximab is chimeric antibody, Adalimumab is humanized antibody), and excellent spy gram monoclonal antibody is anti-human IL-12/23p40 humanized antibodies.These psoriasises are controlled It is entirely Japan's approval to treat agent.In table 3, the drug withdrawal reason of these medicines curative effect of medication apply from the beginning with regard to it is inadequate when Be given by " constitutional failure ", and when curative effect of medication is given when weakening after continuous administration by " secondary failure ".In medicine Thing is applied and is not as curative effect and is because serious side effect to reach the intolerable degree of experimenter and needs the feelings being discontinued It is inadequate that condition is described as toleration in table 3.Judge that AM-14 treatments are effective when the CGI of the 52nd week is 2 or 1, and work as CGI and comment It is invalid to be judged to when point not being 2 and 1.

[table 3]

Curing psoriasis agent uses history

As shown in table 3, the AM-14 administrations show and (original are not being responded to infliximab or adalimumab Send out property failure or secondary failure) four experimenters (A, B, C and E) in three (experimenter A, B and C) have response to treatment. As shown in the result of experimenter D, find AM-14 can continuous administration 50 weeks, and or even to apply infliximab and Ah It is subjected to serious side effects up to wooden monoclonal antibody and is judged as the experimenter inadequate to infliximab and adalimumab toleration Also show that response to treatment.

As these results are proved, show for because the anti-TNF-α antibody such as infliximab and A Damu are mono- It is anti-do not act on or cause serious side effects and can not be with the pustular psoriasiss experimenter of anti-TNF-α antibody treatment, AM- 14 continuous administration and can improve psoriasises symptom in a long time.

Embodiment 4

Response to treatment of the AM-14 to the erythroderma psoriaticum patient of administering anti-TNF-Alpha antibodies

There is three erythroderma psoriaticum patients for participating in the clinical trial of embodiment 1 anti-TNF-α antibody to apply history. PASI (psoriasises area and Severity Index) scoring of these experimenters in certain hour process is measured, it is psoriatic The order of severity is measured.As a result present in figure 3.PASI is scored and is calculated using the evaluation methodology be given in table 4.

[table 4]

PASI score calculation methods

As described in Figure 3, as application times increase, the PASI scorings of each experimenter are reduced.In experimenter F, H and G, PASI scorings are down to close 0 at the 10th, 12 and 48 weeks for having applied for the first time respectively.As these results are proved, AM-14 is shown For the erythroderma psoriaticum patient for having applied the anti-TNF-α antibody has response to treatment.

Table 5 provides the curing psoriasis agent of these three experimenters and uses history.

[table 5]

The curing psoriasis agent of experimenter uses history

Table 5 follows the identical definition that table 3 is used.When each patient the 52nd week PASI scoring less than apply AM-14 it When the PASI of front tolerance scores, judge that AM-14 treatments are effective., it can be seen that AM-14 is shown single to Ah 's wood in table 5 Also treat in the anti-patient (experimenter H) not responded to effective.Although administration infliximab is in experimenter (experimenter G) Generation serious side effects, and experimenter G is to be determined the experimenter inadequate to infliximab toleration, but AM-14 energy Enough continuous administration 50 weeks, and show response to treatment.

As these results are proved, show for because the anti-TNF-α antibody such as infliximab and A Damu are mono- It is anti-do not act on or cause serious side effects and can not with the erythroderma psoriaticum experimenter of anti-TNF-α antibody treatment, AM-14 interior continuous administration and can improve psoriasises symptom over a long time.

Although the present invention is described in detail and with reference to its specific embodiment, without departing from the spirit and scope Under can wherein make various changes and modifications, will be apparent to those skilled in the art.

The application is U.S. Provisional Patent Application No.62/041 based on the submission on the 26th of August in 2014, on 862, institute The entire content for stating temporary patent application is incorporated herein.All references cited herein is with its entirety With reference to.

[the free text of sequence table]

SEQ ID NO：The description of 1- artificial sequences：The aminoacid sequence of AM-14_HCDR1

SEQ ID NO：The description of 2- artificial sequences：The aminoacid sequence of AM-14_HCDR2

SEQ ID NO：The description of 3- artificial sequences：The aminoacid sequence of AM-14_HCDR3

SEQ ID NO：The description of 4- artificial sequences：The aminoacid sequence of AM-14_LCDR1

SEQ ID NO：The description of 5- artificial sequences：The aminoacid sequence of AM-14_LCDR2

SEQ ID NO：The description of 6- artificial sequences：The aminoacid sequence of AM-14_LCDR3

SEQ ID NO：The description of 7- artificial sequences：The aminoacid sequence of AM-14_VH

SEQ ID NO：The description of 8- artificial sequences：The aminoacid sequence of AM-14_VL.

Sequence table

<110>Kylin-Amgen Inc

<120>Received the Therapeutic Method of the psoriatic of anti-TNF-α antibody therapy

<130> SCT170534-40

<150> US 62/041,862

<151> 2014-08-26

<160> 8

<170> PatentIn version 3.3

<210> 1

<211> 5

<212> PRT

<213> Artificial

<220>

<223> Description of artificial sequence; amino acid sequence of

AM-14_H_CDR1

<400> 1

Arg Tyr Gly Ile Ser

1 5

<210> 2

<211> 17

<212> PRT

<213> Artificial

<220>

<223> Description of artificial sequence; amino acid sequence of

AM-14_H_CDR2

<400> 2

Trp Ile Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln

1 5 10 15

Gly

<210> 3

<211> 7

<212> PRT

<213> Artificial

<220>

<223> Description of artificial sequence; amino acid sequence of

AM-14_H_CDR3

<400> 3

Arg Gln Leu Tyr Phe Asp Tyr

1 5

<210> 4

<211> 11

<212> PRT

<213> Artificial

<220>

<223> Description of artificial sequence; amino acid sequence of

AM-14_L_CDR1

<400> 4

Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala

1 5 10

<210> 5

<211> 7

<212> PRT

<213> Artificial

<220>

<223> Description of artificial sequence; amino acid sequence of

AM-14_L_CDR2

<400> 5

Asp Ala Ser Thr Arg Ala Thr

1 5

<210> 6

<211> 9

<212> PRT

<213> Artificial

<220>

<223> Description of artificial sequence; amino acid sequence of

AM-14_L_CDR3

<400> 6

Gln Gln Tyr Asp Asn Trp Pro Leu Thr

1 5

<210> 7

<211> 116

<212> PRT

<213> Artificial

<220>

<223> Description of artificial sequence; amino acid sequence of

AM-14_VH

<400> 7

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gln Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 8

<211> 107

<212> PRT

<213> Artificial

<220>

<223> Description of artificial sequence; amino acid sequence of

AM-14_VL

<400> 8

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

Claims

1. the therapeutic agent of pustular psoriasiss or erythroderma psoriaticum, it is applied to apply anti-TNF-α antibody Psoriatic, the therapeutic agent is comprising IL-17RA antagonisies as active component.

2. therapeutic agent according to claim 1, wherein the anti-TNF-α antibody is selected from adalimumab, Infliximab Monoclonal antibody, Polyethylene Glycol combine at least one of match trastuzumab, match trastuzumab and goli mumab.

3. therapeutic agent according to claim 1 and 2, wherein the IL-17RA antagonisies are anti-IL-17RA antibody or it is anti- Body fragment.

4. therapeutic agent according to claim 3, wherein the anti-IL-17RA antibody selected from it is following a) and b)：

A) monoclonal antibody, wherein the complementary determining region of the weight chain variable district (hereinafter referred to as VH) of the antibody is (hereinafter referred to as CDR) 1, CDR2 and CDR3 include respectively SEQ ID NO：1st, the aminoacid sequence shown in 2 and 3, and the light chain of the antibody CDR1, CDR2 and CDR3 of variable region (hereinafter referred to as VL) includes respectively SEQ ID NO：4th, the aminoacid sequence shown in 5 and 6 Row；With

B) monoclonal antibody, wherein the VH of the antibody includes SEQ ID NO：The aminoacid sequence shown in 7, and it is described anti- The VL of body includes SEQ ID NO：The aminoacid sequence shown in 8.

5. the Clinical Global of the therapeutic agent according to any one of Claims 1-4, wherein patient after the therapeutic agent is applied Impression (hereinafter also referred to CGI) becomes 2 or 1.

6. the psoriasises face of the therapeutic agent according to any one of claim 1 to 5, wherein patient after the therapeutic agent is applied Product and Severity Index (hereinafter referred to as PASI) scoring are less than the PASI scorings applied before the therapeutic agent.

7. curing psoriasis agent, it is applied to the psoriatic that can not be treated with anti-TNF-α antibody, and the therapeutic agent is included IL-17RA antagonisies are used as active component.

8. therapeutic agent according to claim 7, wherein the patient that can not be treated with anti-TNF-α antibody be to described anti- TNF-α antibody is not responding to or the patient inadequate to the anti-TNF-α antibody toleration.

9. the therapeutic agent according to claim 7 or 8, the anti-TNF-α antibody is selected from adalimumab, Infliximab list Anti-, Polyethylene Glycol combines at least one of match trastuzumab, match trastuzumab and goli mumab.

10. the therapeutic agent according to any one of claim 7 to 9, wherein the IL-17RA antagonisies are anti-IL-17RA resisting Body or its antibody fragment.

11. therapeutic agents according to claim 10, wherein the anti-IL-17RA antibody selected from it is following a) and b)：

A) monoclonal antibody, wherein CDR1, CDR2 and CDR3 of the VH of the antibody include respectively SEQ ID NO：1st, in 2 and 3 The aminoacid sequence of display, and CDR1, CDR2 and CDR3 of the VL of the antibody includes respectively SEQ ID NO：4th, in 5 and 6 The aminoacid sequence of display；With

12. therapeutic agents according to any one of claim 7 to 11, wherein the psoriasises be selected from psoriasis vulgarises, At least one of psoriatic arthritis, pustular psoriasiss, erythroderma psoriaticum and psoriasis punctata.

The CGI of 13. therapeutic agents according to any one of claim 7 to 12, wherein patient after the therapeutic agent is applied becomes Into 2 or 1.

The PASI of 14. therapeutic agents according to any one of claim 7 to 13, wherein patient after the therapeutic agent is applied is commented Divide less than the PASI scorings applied before the therapeutic agent.

The Therapeutic Method of 15. pustular psoriasiss or erythroderma psoriaticum, it is included to having applied anti-TNF-α antibody Psoriatic applies IL-17RA antagonisies.

16. methods according to claim 15, wherein the anti-TNF-α antibody is selected from adalimumab, Infliximab Monoclonal antibody, Polyethylene Glycol combine at least one of match trastuzumab, match trastuzumab and goli mumab.

17. methods according to claim 15 or 16, wherein the IL-17RA antagonisies be anti-IL-17RA antibody or its Antibody fragment.

18. methods according to claim 17, wherein the anti-IL-17RA antibody selected from it is following a) and b)：

19. methods according to any one of claim 15 to 18, wherein patient are after the IL-17RA antagonisies are applied CGI becomes 2 or 1.

20. methods according to any one of claim 15 to 19, wherein patient are after the IL-17RA antagonisies are applied PASI scorings are less than the PASI scorings applied before the antagonist.

21. methods according to any one of claim 15 to 20, wherein applying the IL- with the dosage of 140mg or bigger 17RA antagonisies.

22. methods according to any one of claim 15 to 21, wherein applying the IL- with the dosage of 140mg or 210mg 17RA antagonisies.

23. methods according to any one of claim 15 to 22, wherein at the 1st day, the 1st week and the 2nd week and every thereafter Biweekly, the IL-17RA antagonisies are applied with the dosage of 140mg or 210mg.

24. curing psoriasis methods, it includes short of money to applying IL-17RA with the psoriatic of anti-TNF-α antibody treatment Anti-agent.

25. methods according to claim 24, wherein the patient that can not be treated with anti-TNF-α antibody is to described anti- Invalid or inadequate to the anti-TNF-α antibody toleration patient of TNF-α antibody.

26. methods according to claim 24 or 25, wherein the anti-TNF-α antibody is selected from adalimumab, Ying Fu Sharp former times monoclonal antibody, Polyethylene Glycol combine at least one of match trastuzumab, match trastuzumab and goli mumab.

27. the method according to any one of claim 24 to 26, wherein the IL-17RA antagonisies are anti-IL-17RA resisting Body or its antibody fragment.

28. methods according to claim 27, wherein the anti-IL-17RA antibody selected from it is following a) and b)：

29. methods according to any one of claim 24 to 28, wherein the psoriasises are selected from psoriasis vulgarises, silver At least one of the sick arthritis of bits, pustular psoriasiss, erythroderma psoriaticum and psoriasis punctata.

30. the method according to any one of claim 24 to 29, wherein patient are after the IL-17RA antagonisies are applied CGI becomes 2 or 1.

31. methods according to any one of claim 24 to 30, wherein patient are after the IL-17RA antagonisies are applied PASI scorings are less than the PASI scorings applied before the antagonist.

32. methods according to any one of claim 24 to 31, wherein applying the IL- with the dosage of 140mg or bigger 17RA antagonisies.

33. methods according to any one of claim 24 to 32, wherein applying the IL- with the dosage of 140mg or 210mg 17RA antagonisies.

34. methods according to any one of claim 24 to 33, wherein at the 1st day, the 1st week and the 2nd week and every thereafter Biweekly, the IL-17RA antagonisies are applied with the dosage of 140mg or 210mg.